CN115068458A - 戊酸在制备防治糖尿病药物中的应用 - Google Patents
戊酸在制备防治糖尿病药物中的应用 Download PDFInfo
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- CN115068458A CN115068458A CN202210869612.9A CN202210869612A CN115068458A CN 115068458 A CN115068458 A CN 115068458A CN 202210869612 A CN202210869612 A CN 202210869612A CN 115068458 A CN115068458 A CN 115068458A
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Abstract
本发明提供了戊酸在制备防治糖尿病药物中的应用,属于糖尿病治疗技术领域。本发明提供了戊酸的新用途,提供了戊酸具有防治2型糖尿病的作用。
Description
技术领域
本发明属于糖尿病治疗技术领域,尤其涉及戊酸在制备防治糖尿病药物中的应用。
背景技术
糖尿病的部分发病原因是功能性胰腺细胞,即产生胰岛素的胰岛β细胞数量不足。2型糖尿病β细胞数量减少40%-60%,而1型糖尿病β细胞数量减少70%-97%。人和啮齿类动物一样,在出生前后一个短暂段时间内胰腺β细胞数量迅速增加,但在成熟期后,自然条件下β细胞基本无法通过自我复制和增殖来增加数量。
目前尚无能够诱导人类胰岛β细胞增殖的市售药物。正在研究中的促人类β细胞再生分子,如骨保护素、λ-氨基丁酸等,Ki67或BrdU实验结果显示其细胞增殖率低于0.5%~1%。因此,如果能研发一种能够有效促进胰腺β细胞数量迅速增加的药物或产品,将能够为世界糖尿病的高危人群、糖尿病前期人群,及糖尿病患者的预防和治疗,带来新的希望。
发明内容
有鉴于此,本发明的目的在于提供戊酸在制备防治糖尿病药物中的应用,提供了戊酸的新用途,用来防治2型糖尿病。
为了实现上述发明目的,本发明提供了以下技术方案:
本发明提供了戊酸在制备防治糖尿病药物中的应用。
优选的,所述糖尿病包括2型糖尿病。
优选的,将所述戊酸制备成戊酸盐,将所述戊酸盐用于治疗糖尿病。
优选的,所述戊酸盐包括戊酸钠。
本发明还提供了戊酸在制备促进胰岛β细胞增殖药物中的应用。
本发明的有益效果为:
通过动物实验和细胞实验等体外实验发现,戊酸通过促进胰腺细胞增殖和分化、促进胰岛素分泌、改善胰岛素敏感性等方式对葡萄糖稳态起到积极的作用效果。同时,将戊酸对血糖的改善效果与另一种结构相似、研究更为广泛的短链脂肪酸-丁酸、糖尿病常用药物二甲双胍和同样具有促进胰岛细胞增值效果的DYRK1A抑制剂-Harmine相对比,戊酸显示出了更优的作用效果。
另外,在探究戊酸改善血糖稳态机制的过程中,利用蛋白质组学发现,戊酸能上调Pdpk1的表达,从而激活PI3K/Akt这一经典的胰岛素信号通路,进而发挥了抑制细胞凋亡、促进生长增殖,增加葡萄糖的转运和摄取,以及促进脂肪和糖原合成的作用,这也为戊酸的作用效果提供了坚实的理论依据。
附图说明
图1为摄食量记录;
图2为体重记录;
图3为空腹血糖变化情况;
图4为小鼠胰腺组织切片HE染色(200μm);
图5为小鼠胰腺组织切片HE染色(50μm);
图6为小鼠胰腺组织免疫组化ERK染色;
图7为小鼠胰腺组织切片免疫荧光胰岛素(红)/Ki67(绿)/DAPI(蓝);
图8为小鼠胰腺组织切片免疫荧光胰岛素(红)/胰高血糖素/DAPI;
图9为db/db小鼠摄食量记录情况;
图10为db/db小鼠体重变化情况;
图11为db/db小鼠血糖相关指标变化情况;
图12为db/db小鼠胰岛组织HE染色;
图13为db/db小鼠胰岛组织胰岛素/胰高血糖素免疫荧光;
图14为db/db小鼠胰岛组织Ki367/胰岛素免疫荧光;
图15为CCK-8细胞活性实验结果;
图16为EdU-488细胞增殖实验结果,上:Beta-TC-6细胞系,下:小鼠胰岛β原代细胞;
图17为TUNEL细胞凋亡检测实验和流式细胞分析技术实验结果,上:Beta-TC-6细胞系,下:小鼠胰岛β原代细胞;
图18为胰岛素分泌能力实验结果,上:Beta-TC-6细胞系,下:小鼠胰岛β原代细胞;
图19为小鼠胰腺组织蛋白质组学结果;
图20为小鼠胰腺组织蛋白质组学结果;
图21为胰岛素信号通路;
图22为WB和ELISA验证差异蛋白表达情况。
具体实施方式
本发明提供了戊酸在制备防治糖尿病药物中的应用。在本发明中,所述糖尿病优选包括2型糖尿病。本发明优选将所述戊酸制备成戊酸盐,将所述戊酸盐用于治疗糖尿病。本发明对将戊酸制备成戊酸盐的制备方法没有特殊限定,本领域技术人员采用常规方法制备即可。在本发明中,所述戊酸盐优选包括戊酸钠。本发明对所述药物的剂型、制备方法以及药物中戊酸的含量没有特殊限定,本领域技术人员根据常规即可。
在本发明中,戊酸的化学式为CH3(CH2)3COOH,CAS号为109-52-4,结构式如下:
在本发明中,所述戊酸钠的化学式为C5H9NaO2,CAS号为6106-41-8,结构式如下:
本发明还提供了戊酸在制备促进胰岛β细胞增殖药物中的应用。本发明对所述药物的剂型、制备方法以及药物中戊酸的含量没有特殊限定,本领域技术人员根据常规即可。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
戊酸(Valeric acid),小鼠灌胃剂量为75mg/kg/d,即为戊酸的1/8LD50剂量,在给予灌胃前将戊酸与碳酸氢钠融合反应,配置为戊酸钠溶液,直至溶液的酸碱度pH=7.0。根据药理学和毒理学的专业知识,换算为成人每日用量约为550~600mg/d。
本实施例中所使用的戊酸标准品采购自Sigma-Aldrich公司,货号为240370,纯度≥99.0%,状态为液体。碳酸氢钠标准品采购自Sigma-Aldrich公司,货号为S5761,纯度99.5-100.5%,状态为粉末。
在第一阶段高脂模型小鼠动物实验中,首先从辽宁长生生物技术股份有限公司订购无特定病原体(SPF级)6-8周的雄性C57BL/6J小鼠,验动物饲料订购于北京科澳协力饲料有限公司,包括小鼠AIN-93M维持饲料和脂肪供能比为45%的高脂饲料,两种饲料的营养素构成均按照美国农业部推荐的啮齿类实验动物饲料配方,AIN-93M维持饲料为常温保存,45%供能比的高脂饲料为-20℃低温保存。
动物实验研究按照哈尔滨医科大学的实验动物管理的委员会所要求执行的规章制度而进行开展,于哈尔滨医科大学公共卫生学院清洁级实验动物中心实验室内饲养,实验室条件为:温度21.0(±1.5)摄氏度、相对湿度50(±5)%、12:12小时日光灯交替照明、自由摄取饲料和饮用蒸馏水。在接收到6-8周龄SPF级实验动物C57BL6/J小鼠后,单笼饲养,被安排自由引用蒸馏水和动物饲料,进行为期一周的适应性喂养。随后对小鼠进行称量体重,按照小鼠体重数值随机分为4个实验组,分别饲喂AIN-93M维持饲料和45%高脂饲料,以及进行磷酸缓冲盐溶液(PBS)和不同代谢物溶液的口饲灌胃处理,具体分组方式如下:①普通饲料喂养组(Control组,饲喂AIN-93M饲料)、②45%高脂饲料喂养PBS灌胃组(HFD+PBS组)、③45%高脂饲料喂养戊酸灌胃组(HFD+VA组)、④45%高脂饲料喂养丁酸灌胃组(HFD+BU组),每组12只小鼠。
实验动物饲养期间,每天使用电子秤进行小鼠撒食量和剩食量的称重记录和更换新鲜饲料,并计算每日摄食量,每晚将适量的脂肪供能比45%的高脂饲料从-20摄氏度的冰箱冷冻层中转移至4摄氏度的保鲜层,并在每次给食前将维持饲料和高脂饲料一同在室温条件下放置1小时。每3天更换一次新鲜的蒸馏饮用水。每周进行一次小鼠体重的称量和记录,并更换高压消毒后洁净的动物垫料。小鼠的灌胃操作每天进行一次,灌胃溶剂在每次操作前现用现配,灌胃剂量中的实验剂量:PBS按5mg/kg体重给予,戊酸和丁酸分别按75mg/kg体重给予,由于戊酸和丁酸的酸性较强直接进行灌胃容易造成消化道损伤,因此将戊酸和丁酸分别制备成戊酸钠和丁酸钠进行灌喂。根据《Onyszkiewicz,Maksymilian et al.“Valeric acid lowers arterial blood pressure in rats.”European journal ofpharmacology vol.877(2020):173086.doi:10.1016/j.ejphar.2020.173086》文献中大鼠静脉注射剂量为0.15mmol/kg,依据徐淑云主编的<<药理实验方法学>>中口服与静脉注射剂量换算,以及大小鼠折算的等效剂量比值最终确定戊酸剂量为75mg/kg,约等于戊酸半数致死剂量的1/8符合毒理学中安全范围。
为了检测小鼠的血糖稳态水平和胰岛素功能,进行小鼠口服糖耐量实验(OGTT),在实验进行前一晚,对实验小鼠进行禁食不禁水16小时,并从饲养室转移至洁净级实验操作室,以便动物适应环境。OGTT实验开始前对每只小鼠的体重进行精准称量,按2mg/g体重计算葡萄糖注射剂量,在灌胃注入葡萄糖后的0分钟、15分钟、30分钟、60分钟、120分钟时分别在尾部进行剪尾采血。弃去剪尾后的第一滴血,然后使用Accu-Chek血糖仪(美国罗氏诊断)连续检测血糖浓度(mmol/L)。在对实验小鼠进行取材前一晚禁食12小时,使用含有10%水合氯醛溶液腹腔注射进行麻醉处理,剪开小鼠腹腔后,采用心尖取血的方式采集血液,并处死实验小鼠。采集完血液样本后室温静置2小时后,经3000转/分钟离心15分钟吸取上层血清,立即进行血清生化检测。在采集完血液样本后,为防止胰腺溶解,立即剪下小鼠胰腺组织,并按胰头、胰尾两部分分开保存。随后摘取小鼠其他组织。拍照留存小鼠各部分组织形态图片,分别称重并精准记录组织重量。随后将摘取得到的组织分为两部分,一部分分装至EP管中后立即置于液氮中快速冷冻,随后转移至-80℃冰箱冷冻保存;另一部分分装至装有4%多聚甲醛的EP管中固定,用于后期制作病理组织切片。
后期试验过程中,为了观察动物组织病理形态,制作了小鼠组织石蜡切片,进行了石蜡切片HE染色、免疫组织化学染色和免疫荧光技术染色。并且,将戊酸干预组与对照组的小鼠胰尾组织从-80℃冰箱取出,进行了动物组织TMT标记定量蛋白质组检测,并对差异蛋白进行了动物组织蛋白质印迹法(WesternBlot)实验,和实时荧光定量聚合酶链式反应(qRT-PCR)实验,以对实验结果进行验证。
最后,为了检测干预过程中是否造成肿瘤侵袭,检测和比较小鼠血清中的糖类抗原(CA 19-9)和癌胚抗原(CEA)的含量,使用全自动电化学发光免疫分析系统8000(美国罗氏),利用电化学发光免疫分析(ECLIA)进行测定。
在本实施例的细胞实验阶段过程中,从武汉普诺赛生命科技有限公司购置小鼠胰岛素瘤胰岛β细胞(Beta-TC-6)细胞系,和小鼠胰岛β原代细胞,用于开展相关实验研究。
采用细胞计数试剂盒8(Cell Counting Kit 8,CCK-8)是检测细胞活性的一种方便而可靠的方法。本实施例还将采用BeyoClickTMEdU-488试剂盒检测细胞增殖水平,EdU(5-ethynyl-2'-deoxyuridine)是一种胸腺嘧啶脱氧核苷类似物,可在细胞增殖过程中替代T以浸润复制的DNA分子。通过EdU与Fluor 488荧光染料的特异性反应检测DNA复制活性,可准确检测EdU标记进而反映细胞的增殖情况。本实施例采用免疫荧光法(免疫细胞化学)检测细胞中Ki-67的表达情况,以及参考一步法TUNEL细胞凋亡检测试剂盒(红色荧光)的方法对细胞凋亡情况进行分析。同时,本实施例将利用流式细胞分析技术,完成细胞周期的检测和细胞凋亡检测。
以下列药物为比较例:
1、现有药物作为阳性对照的比较例
(1)高脂喂养C57BL6/J小鼠
丁酸钠灌胃干预组:75.0mg/kg
(2)2型糖尿病模型db/db小鼠
丁酸钠灌胃干预组:75.0mg/kg
Harmine灌胃干预组:10.0mg/kg
二甲双胍灌胃干预组:100.0mg/kg
(3)小鼠胰岛素瘤胰岛β细胞(Beta-TC-6)细胞系
丁酸钠干预组:1.0mmol/L
Harmine干预组:10.0μmmol/L
(4)小鼠胰岛β原代细胞
丁酸钠干预组:1.0mmol/L
Harmine干预组:10.0μmmol/L
2、以对照试验作为比较例
(1)高脂喂养C57BL6/J小鼠
普通饲料喂养组、高脂饲料PBS灌胃组
(2)2型糖尿病模型db/db小鼠
对照喂养组、PBS灌胃组
(3)小鼠胰岛素瘤胰岛β细胞(Beta-TC-6)细胞系
空白对照组、软脂酸(Palmitic acid,PA)干预阴性对照组
(4)小鼠胰岛β原代细胞
空白对照组、PA干预阴性对照组。
结果如下:
(一)开展动物实验探究戊酸对血糖稳态的影响
食用正常饲料的小鼠(NC组)体重变化8周内增长幅度较小,食用高脂饲料的小鼠(HF-PBS组)体重呈现显著上升趋势,但戊酸干预下的小鼠(HF-V组)从干预后的第五周开始体重呈下降趋势,第六周后体重明显低于HF-PBS组(图1),但整个干预期间各组摄食量并无明显差异(图2)说明HF-V组小鼠体重的降低不是由于戊酸对小鼠饮食变化引起的。在干预8周时间点,检测小鼠的空腹血糖、空腹胰岛素含量,及OGTT-2h血糖曲线下面积,HF-V组均显著低于HF-PBS对照组,说明戊酸可能在改善机体血糖稳态方面起着重要作用(图3)。
在对小鼠胰腺组织病理学结果进行分析时,发现HF-PBS组的胰岛面积、胰岛数量及胰岛β细胞数量与对照组相比均有变少及变小的现象,但经过戊酸干预后,HF-V组小鼠的胰岛面积明显变大,胰岛数量增加(图4),并且在胰岛中的β细胞数量也显著增加(图5)。另外,对石蜡切片进行细胞外调节蛋白激酶ERK(extracellular regulated proteinkinases)染色后发现,ERK阳性区域比例显著增加,说明胰腺细胞增殖生长、有丝分裂活跃(图6);在对小鼠胰腺组织切片进行胰岛素/Ki67/DAPI免疫荧光染色后发现,戊酸干预组小鼠胰腺中Ki67染色细胞核数量显著增加,表明处于增殖分裂期细胞增加(图7);经过胰岛素/胰高血糖素/DAPI免疫荧光染色后发现,戊酸干预组小鼠胰腺中胰岛素分泌比例显著增加,表明胰岛β细胞功能上调(图8)。
在观察到戊酸能够促进胰岛细胞有丝分裂的现象后,为了验证是否会有肿瘤的产生,对小鼠血清中CEA(癌胚抗原)、CA19-9(低聚糖肿瘤相关抗原)等胰腺癌特异性肿瘤标志物进行了检测,发现HF+PBS与HF+VA小鼠血清中CEA<0.200U/mL、CA19-9<0.600U/mL,表明小鼠未发生癌症侵袭,胰岛细胞数量增加属于生理性细胞增殖。
(二)动物实验是以Leptinreceptor基因缺陷鼠-db/db小鼠(购买于南京君科生物科技有限公司)为实验对象,观察戊酸对糖尿病的治疗效果。发现,各组实验小鼠的摄食量无显著差异(图9),而戊酸组的体重与PBS对照组相比显著下降(图10)。尤其在对血糖稳态相关指标进行检测时,发现,与PBS对照组相比,仅戊酸组的空腹血糖发生了显著下降,降低幅度达到近10mmol/L;OGTT曲线变化情况显示了,戊酸干预组的曲线下面积最小、显著优于二甲双胍组和Harmine阳性药物组;同时,胰岛素的变化情况也显示,戊酸的胰岛素分泌情况最优,优于Harmine组,且二甲双胍组与PBS对照组基本无差异(图11)。
同样对db/db小鼠的胰腺组织进行了病理组织学检测,发现戊酸干预组小鼠的胰岛面积和胰岛细胞均发生了显著的增加(图12),胰岛素/胰高血糖素的比例显著增加,说明胰岛素分泌情况显著改善(图13),对Ki67/胰岛素进行染色后发现,Ki67(+)比例显著增加,说明戊酸干预组的小鼠胰腺细胞有丝分裂增加(图14)。
(三)开展细胞实验探究戊酸对血糖稳态的影响
实验结果如下:
将戊酸制备成戊酸钠再进行实验,在进行CCK-8细胞活性实验的过程中,设置了梯度浓度为0.1mmol/L、0.2mmol/L、0.5mmol/L、1mmol/L、2.5mmol/L、5mmol/L、10mmol/L、20mmol/L、50mmol/L、100mmol/L的戊酸钠溶液(换算成戊酸浓度分别为0.08mmol/L、0.16mmol/L、0.40mmol/L、0.8mmol/L、2mmol/L、4mmol/L、8mmol/L、16mmol/L、40mmol/L、80mmol/L)分别对Beta-TC-6细胞和小鼠胰岛β原代细胞干预12小时、24小时和48小时,通过CCK-8试剂盒的检测结果,分别计算不同浓度、不同干预时长的戊酸钠对胰岛细胞活性的影响效果(如图15)。根据细胞的活性水平,最终确定戊酸钠干预浓度1mmol/L,干预时长12小时。
通过EdU-488细胞增殖实验,分别对Beta-TC-6细胞和小鼠胰岛β原代细胞进行检测:发现软脂酸PA干预后EdU(+)细胞比例显著降低,细胞增殖水平显著降低;在PA干预后继续对细胞进行戊酸钠SV干预,细胞中EdU(+)细胞比例较PA组显著回升,细胞增殖水平显著提高(图16)。
通过TUNEL细胞凋亡检测实验,PA干预后,凋亡细胞比例显著增加,SV干预后,凋亡细胞比例有所下降。利用流式细胞分析技术对Beta-TC-6细胞:PA干预后,Q2象限(晚期凋亡)和Q3象限(早期凋亡)比例显著增加,SV干预后,凋亡细胞比例明显降低。戊酸钠SV能够在一定程度上削弱PA诱导的细胞凋亡(图17)。
通过胰岛素分泌能力实验,比较各组在无糖、低糖(2.8mmol/L)和高糖(20mmol/L)浓度下产生胰岛素水平。PA干预后,分泌胰岛素能力显著下降;SV、SB和Harmine干预后,高糖环境刺激下的胰岛素分泌水平均显著提高,并且戊酸钠促进细胞胰岛素分泌能力更为显著(图18)。
(四)戊酸对血糖状态改善的机制探索
在对高脂模型小鼠HFD+PBS、HFD+VA组的胰腺组织进行TMT蛋白质组学检测的过程中发现,经PCA分析,两组总体蛋白差异显著;经CV分析显示,表明两组重复性良好后。通过GO、KEGG数据库功能注释,富集得到能量及糖脂代谢、糖原合成、氧化还原和磷酸化等代谢通路(图19)。
依据FC>1.2或<0.8,且p-FDR<0.05标准,确定HFD+PBS组和HFD+VA组小鼠胰腺组织中差异蛋白:上调16个、下调18个。结合差异蛋白互作网络分析,确定戊酸干预后在小鼠胰腺组织中表达显著升高的差异蛋白3-磷酸肌醇依赖性蛋白激酶1(Pdpk1)(图20)。
PI3K(磷脂酰肌醇3-激酶)途径是胰岛素代谢的最主要途径,其中Pdpk1起核心作用,激活蛋白激酶家族,促进糖的利用和转化,抑制糖原分解;介导β细胞生存通路,促进β细胞生长增殖(图21)。
并且,通过WB和ELISA验证小鼠胰腺组织中PI3K/Pdpk1/Akt胰岛素代谢通路关键蛋白表达水平:戊酸组小鼠胰腺组织中Pdpk1、Akt、p-Akt、mTOR、p-mTOR、以及PIP3的表达均显著升高(p value<0.05);同时,验证细胞增殖和分化通路中的经典蛋白的表达水平:PDX1、Nkx6.1、MafA、FoxO1A、ERK1/2、p-ERK1/2的表达均显著升高(图22)。
综上所述,戊酸显著回复胰岛β细胞数量,提高胰岛素分泌水平,降低血糖,从而发挥治疗糖尿病的作用。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.戊酸在制备防治糖尿病药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述糖尿病包括2型糖尿病。
3.根据权利要求1所述的应用,其特征在于,将所述戊酸制备成戊酸盐,将所述戊酸盐用于治疗糖尿病。
4.根据权利要求3所述的应用,其特征在于,所述戊酸盐包括戊酸钠。
5.戊酸在制备促进胰岛β细胞增殖药物中的应用。
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